8-sulfo-3-quinoline carboxylic acid compounds

ABSTRACT

This invention relates to a compound of the formula: ##STR1##

This application is a divisional of Ser. No. 08/288,374 filed Aug. 10,1994, now U.S. Pat. No. 5,466,808, which is a continuation-in-part ofSer. No. 08/180,593 filed Jan. 13, 1994, now U.S. Pat. No. 5,430,152,which is a continuation-in-part of PCT/US94/02100 filed Feb. 14, 1994,which is a continuation-in-part of Ser. No. 08/017,583 filed Feb. 16,1993, now abandoned.

BACKGROUND OF THE INVENTION Technical Field

The invention relates a new method for to the preparation of8-sulfo-3-quinolinic carboxylic acids and compositions therefrom.

Background

Heterocyclic compounds of the quinolinic acids are known from theliterature. They are intermediates for a broad class of compounds knownas quinolones which have antibacterial activity. These compounds wereprepared in the late 1930's and the early 1940's by the method of R. G.Gould and W. A. Jacobs, J. Amer. Chem. Soc. 61, 2890 (1939). The methodconsists of the cyclization of diethyl anilinomethylenemalonatederivatives in Dowtherm A, diphenylether at temperatures of 250°-300° C.The starting materials for the cyclization reaction are prepared from asubstituted aniline and diethyl ethoxymethylenemalonate. This method hasbeen employed in a number of syntheses, 4,7-Dichloroquinoline, J. Amer.Chem. Soc. 68, 113 (1946); J. Amer. Chem. Soc. 68, 1204 (1946). 6,7 or 8halo-4-hydroxyquinoline is described in J. Med. Chemistry 21, 268(1978). Other high boiling solvents have been utilized in this reactionas described in German Offenlegungsschrift Nos. 2,343,462 and 2,441,747,U.S. Pat. Nos. 3,149,104 and 3,673,193 and J. Heterocyclic Chem. 21, 673(1984). The use of polyphosphoric acid, sulfuric and acetic acid hasbeen described in J. Org. Chem. Soc. 32, 4155 (1967) and 33, 1218 (1968)and J. Heterocyclic Chem. 27, 1527 (1990). In Pharmaceutical Industry1986, 17 (9) 390-394, the ring closure of the anilinomethylenemalonatederivative is carried out with various Lewis Acid catalysts namelypolyphosphoric ester, polyphosphoric acid, phosphorousoxychloride,phosphorous pentoxide, and a mixture of acetic anhydride and sulfuricacid. The yields obtained with these prior art methods are generallyinferior to those of this invention.

A variation on this reaction is the use of anilinomethylenemeldrum'sacid esters in place of the normal anilinomethylenemalonic acid esters.These materials are more reactive. However, they are much more expensiveto make. Examples of the use of these compounds are given in G.B. Patent1,147,760; J. Prakt. Chemie. 333,267 (1990) and J. Heterocyclic Chem.27, 1527 (1990).

Chloroquine is a quinoline derivative that was found safe for thetreatment of plasmodium falciparum malaria in 1946. It was prepared fromm-chloroaniline and ethyloxalacetate. The resultantm-chloroanilinomaleate or fumarate derivative was cyclized indiphenylether at high temperature. An industrial procedure is describedin Ind. & Eng. Chem (41), 4, 1949, 654-662.

It is advantageous to have a method of preparation that does not utilizeDowtherm A, diphenylether. It is a suspect carcinogen and toxic. Highboiling solvents are difficult to separate from the product andgenerally washing with a low boiling solvent is required to remove thehigh boiling solvent. In some cases, the addition of a low boilinghydrocarbon solvent is also necessary to precipitate the product fromthe diphenyl-ether reaction solvent. This situation creates furtherproblems. It is more difficult to recycle the solvent under theseconditions. It is advantageous to carry out the reaction in a solventthat can be diluted with water and disposed of without presenting anenvironmental hazard. It is also an advantage to use inexpensive,readily available starting materials. These and other advantages areachieved by the invention.

Although polyphosphoric, sulfuric, and acetic acid have been found to beeffective reaction solvents for the cyclization of certain halogensubstituted anilinomethylenemalonates as noted above, they do notgenerally provide the high yields of this invention. The presentinvention provides an efficient process for preparation of novel8-sulfo-3-quinolinic acids in high yield by the cyclization andsulfonation of anilinoacrylic acid esters selected fromanilinomethylenemalonate, anilinofumurate and anilinomaleate thereof ata moderate temperature without the use of environmentally dangerous,toxic solvents.

Summary of the Invention

This invention is directed to 8-sulfo-3-quinolinic acids and a processfor their preparation by the cyclization of anilinomethylenemalonate,anilinofumurate and anilinomaleate esters in a reaction mediumcomprising chlorosulfonic acid or fuming sulfuric acid (oleum) andmixtures thereof. The cyclization and sulfonation of phenylamino esterstakes place with surprising and unexpected ease in the presence ofchlorosulfonic acid or fuming sulfuric acid (oleum).

The process of the invention is illustrated below: ##STR2##

The substituents in the above formulas have the following meanings:

R₁ and R₂ is hydrogen;

R₃ is hydrogen or chloro:

R₄ is hydrogen, F or Cl, preferably R₄ is fluorine;

R₅ is hydrogen, F, Cl, Br, I, C₁ --C₅ alkyl, a halogen substituted C₁ toC₅ alkyl, C₁ to C₅ alkoxy, NO₂ --, R_(n) N-- wherein R is independentlyhydrogen or C₁ to C₅ alkyl and n=2;

R₆ is hydrogen, C₁ --C₅ alkyl, C₃ --C₆ cyclo alkyl or phenyl;

R₇ is hydrogen, C₁ --C₅ alkyl, alkoxycarbonyl wherein said alkoxyportion is a C₁ --C₅ alkoxy or a C₂ --C₆ cycloalkoxy, a phenoxycarbonyl;and

R₈ is hydrogen, C₁ --C₅ alkyl, alkoxycarbonyl, as defined above orphenoxycarbonyl which may be substituted with a halogen or alkyl.

The compositions of the invention may be represent by compounds ofFormula 2 wherein R₇ is carboxyl.

In the process of the invention, the reaction medium compriseschlorosulfonic acid, fuming sulfuric acid (oleum) and mixtures thereof.Fuming sulfuric acid or oleum is a solution of sulfur trioxide inconcentrated sulfuric acid. An oleum reaction medium containing 5-30%sulfur trioxide provided excellent results. The reaction medium may beused in an amount equal to about 2 to 10 times the weight of the FormulaI reactant. The process may be conducted at a temperature of about40°-180° C., more preferably about 60°-150° C., and most preferablyabout 70°-90° C.

Description of the Preferred Embodiments

This invention is directed to substituted8-sulfo-1,4-dihydro-4-oxo-3-quinolinic acids and a method for theirpreparation which comprises heating an ester selected from the groupconsisting of substituted anilinomethylenemalonates, anilinofumuratesand anilinomaleates in the presence of chlorosulfonic acid or fumingsulfuric acid (oleum) and mixtures thereof. The invention provides anefficient environmentally safe process for preparing quinolinic acids inhigh yield under moderate reaction conditions. These phenylamino estersmay be depicted by the following general formula: ##STR3##

The substituents in the above formulas have the following meanings:

R₁ and R₂ are hydrogen;

R₃ is hydrogen, Cl, F, preferably Cl;

R₄ is hydrogen, F or Cl, preferably R₄ is fluorine;

R₅ is hydrogen, F, Cl, Br, I, C₁ --C₅ alkyl, a halogen substituted C₁ toC₅ alkyl, C₁ to C₅ alkoxy, NO₂ --, R_(n) N-- wherein R is independentlyhydrogen or C₁ to C₅ alkyl and n=2;

R₆ is hydrogen, C₁ --C₅ alkyl, C₃ --C₆ cycloalkyl or phenyl;

R₇ is hydrogen, C₁ --C₅ alkyl, alkoxycarbonyl wherein said alkoxyportion is a C₁ --C₅ alkoxy or a C₂ --C₆ cycloalkoxy or, aphenoxycarbonyl; and

R₈ is hydrogen or C₁ --C₅ alkyl.

The anilinomethylenemalonate, anilinofumurate and anilinomaleatestarting materials may be prepared by known methods; e.g. by thecondensation of m-chloroaniline and ethyloxalacetate to producem-chloroanilinomaleate or fumarate (Ind. & Eng. Chem (41 ) 4, 1949,654-662) and by the condensation of a substituted or unsubstitutedaniline with diethyl ethoxy-methylenemalonate to produce diethylanilinomethylenemalonate (J. Amer. Chem. Soc. 68, 113 (1946)).

Exemplary esters are:

diethyl-3-chloro-4,5-difluoroanilinomethylenemalonate;

diethyl-3-chloro-4-fluoroanilinomethylenemalonate;

diethyl-3-chloro-4-fluoroanilinofumurate; and

diethyl-3-chloro-4-fluoroanilinomaleate;

Compounds of the general Formula I are cyclized and sulfonated in achlorosulfonic acid or an oleum reaction medium to yield substituted8-sulfo-3-quinolinic acids and derivatives thereof having the followinggeneral Formula 2: ##STR4##

The substituents R₁ --R₈ are defined above with the alcohol, R₆ OH beingeliminated in the cyclization reaction. The moiety R₇ in the ester formis hydrolyzed to the acid form by drowning the reaction mixture. A mixedreaction medium comprising chlorosulfonic acid and oleum may be employedin the cyclization reaction.

The ring closure reaction is conducted at a temperature from about40°-180° C., more preferably about 60°-150° C., most preferably about70°-90° C. In a preferred embodiment the reaction is conducted at 80° C.The starting material (uncyclized compounds of Formula 1) is heated in areaction medium comprising chlorosulfonic acid; or fuming sulfuric acid,and mixtures thereof. Optionally a diluent may be present such as nitricacid, phosphoric acid or sulfuric acid or an organic solvent such asacetic acid, acetic anhydride propanoic acid or dichlorobenzene andmixtures thereof. The reaction medium is preferably undilutedchlorosulfonic acid or undiluted oleum. The ratio of chlorosulfonic acidor oleum to the starting material (Formula 1 compound) may be in therange of 2:1 to 10:1. The reaction time will depend upon the ease withwhich the ting closure is effected. Generally the reaction is carriedout over a period of about 5 minutes to about 6 hours, preferably about0.5 to about 3 hours. The term, "oleum" or "fuming sulfuric acid" asused in this specification is intended to mean a solution of sulfurtrioxide in concentrated sulfuric acid. Oleum is a common reagent in thechemical industry being readily available in sulfur trioxideconcentrations ranging from 5 to 30 percent.

An appropriate reaction time can be determined by simpleexperimentation. After completion of the reaction period, the desiredquinolinic acid may be recovered by simply drowning the reaction mixturein ice water in a weight ratio of 10:1 to 3:1 (water to acid) preferablyabout 4:1 and filtering the resultant slurry.

The process of the invention may be advantageously used to preparefluorosubstituted quinoline carboxylic acids which are usefulintermediates for the preparation fluorinated quinolone antibacterialcompounds (see for example U.S. Pat. No. 4,528,287). Exemplaryintermediates which can be prepared according to this invention are:

1,4-dihydro-4-oxo-5,6 difluoro-7-chloro-8-sulfo-3-quinolinic acid;

1,4-dihydro-4-oxo-5-methyl-6-fluoro-7-chloro-8-sulfo-3-quinolinic acid;

1,4-dihydro-4-oxo-5,6-difluoro-7-chloro-8-sulfo-3-quinolinic acids;

The following example illustrate the invention. This example isillustrative and not intended to limit the scope of the invention.

EXAMPLES Example 1

This example illustrates a process for preparing8-sulfo-7-chloro-6-fluoro-4-oxo-1,4-dihydro-3-quinolinic acid whereinthe anilinomethylenemalonate starting material of Formula 1 isunsubstituted at the R₁ and R₂ positions i.e. these moieties arehydrogen. In the ring closing process when R₁ and R₂ are hydrogen, notonly does the ring close but the ring position at R₂ is sulfonated.

100 grams of diethyl-3-chloro-4-fluoranilinomethylenemalonate was addedto 400 grams of 20% oleum maintaining the temperature in a range of70°-80° C. When the addition was complete, the reaction mixture washeated at 80° C. for 4 hours. The reaction was allowed to cool to roomtemperature and was drown into 1000 grams of ice. The solid wasfiltered. The solid cake was washed with 3 100 ml portions of ice coldmethanol. The wet cake was dried in a vacuum oven overnight at 60° C.and 62.3 g of 8-sulfo-7-chloro-6-fluoro-4-oxo-1,4-dihydro-3-quinolinicacid was obtained in 61.2% Yield, 99% assay. The structure was verifiedby both I.R. and N.M.R.

The invention also may be conducted in a continuous or batch method andmay be embodied in other specific forms without departing from thespirit or essential characteristics thereof. Through this specificationand the appended claims, a given chemical name or formula is intendedencompass all isomers of said name or formula where such isomers exist.The present embodiments are therefore to be considered in all respectsas illustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription; and all changes which come within the meaning andequivalency of the claims are therefore intended to be embraced therein.

I claim:
 1. A compound of the formula: ##STR5## wherein: R₃ is hydrogenor chloro;R₄ is hydrogen, chloro or fluoro; R₅ is hydrogen, F, Cl, B, I,C₁ --C₅ alkyl, a halogen substituted C₁ to C₅ alkyl, C₁ to C₅ alkoxy,NO₂ --, R_(n) N-- wherein R is independently hydrogen or C₁ to C₅ alkyland n=2; R₇ is carboxy; and R₈ is hydrogen or C₁ --C₅ alkyl.
 2. Acompound according to claim 1 wherein:R₃ is Cl; R₄ is F; R₅ is hydrogen,F, Cl, C₁ --C₅ alkyl, C₁ -- to C₅ alkoxy or NO₂ --.
 3. A compoundaccording to claim 1 wherein R₅ is selected from C₁ to C₅ alkyl and C₁to C₅ alkoxy.
 4. A compound according to claim 1 wherein R₅ is selectedfrom a halogen substituted C₁ to C₅ alkyl.